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Spasticity, a classical clinical manifestation of an upper motor neuron lesion, has been traditionally and physiologically defined as a velocity dependent increase in muscle tone caused by the increased excitability of the muscle stretch reflex. Clinically spasticity manifests as an increased resistance offered by muscles to passive stretching (lengthening) and is often associated with other commonly observed phenomenon like clasp-knife phenomenon, increased tendon reflexes, clonus, and flexor and extensor spasms. The key to the increased excitability of the muscle stretch reflex (muscle tone) is the abnormal activity of muscle spindles which have an intricate relation with the innervations of the extrafusal muscle fibers at the spinal level (feed-back and feed-forward circuits) which are under influence of the supraspinal pathways (inhibitory and facilitatory). The reflex hyperexcitability develops over variable period of time following the primary lesion (brain or spinal cord) and involves adaptation in spinal neuronal circuitries caudal to the lesion. It is highly likely that in humans, reduction of spinal inhibitory mechanisms (in particular that of disynaptic reciprocal inhibition) is involved. While simply speaking the increased muscle stretch reflex may be assumed to be due to an altered balance between the innervations of intra and extrafusal fibers in a muscle caused by loss of inhibitory supraspinal control, the delayed onset after lesion and the frequent reduction in reflex excitability over time, suggest plastic changes in the central nervous system following brain or spinal lesion. It seems highly likely that multiple mechanisms are operative in causation of human spasticity, many of which still remain to be fully elucidated. This will be apparent from the variable mechanisms of actions of anti-spasticity agents used in clinical practice.
Spasticity is a common phenomenon seen in neurologic disorders that result in loss of mobility and may produce pain due to muscle spasms. It is a state of sustained increase in tone of a muscle when it is passively lengthened.
In simple terms of clinical neurology, spasticity is defined as increased resistance to passive movement due to a lowered threshold of tonic and phasic stretch reflexes (Burke et al., 1972).
Physiologically spasticity is defined as a motor disorder characterized by a velocity dependent increase in the tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflexes as one component of the upper motor neuron (UMN) syndrome (Lance, 1980). The velocity dependent increase in resistance to passive stretch often melts suddenly resulting in clasp-knife phenomenon. The definition of spasticity was further elaborated by addition of several features of spastic paresis to form a more comprehensive picture of UMN syndrome which are described below (Young, 1989; Delwaide and Gerard, 1993).
In the pathophysiology of spasticity and spastic paretic syndrome there are two broad categories of inter-related influencing mechanisms namely:
Before discussing spinal mechanisms of spasticity. “Motor control system” and “Motor functions of the spinal cord”, are summarized below.
This system has the following components
Motor functions are basically dependent on the following factors:
Interneuron systems involved in the stretch reflex arc and in the pathophysiology of spasticity are discussed below.
Current hypotheses stress more on alterations in inhibitory mechanisms in spinal neuronal circuitry than an excitatory processes although both may be inter-related in a patient with spasticity.
Figure Figure22 illustrates the spinal reflex circuits that could be involved in the development of spasticity. The monosynaptic Ia excitation which underlies the dynamic and tonic components of the stretch reflex may be inhibited by various spinal reflexes pathways.
The changes in reflex transmission in these pathways may depend both on an altered supraspinal drive (if any remains) and on secondary changes at cellular level in the spinal cord below the lesion which may include:
The importance of supraspinal and suprasegmental control of spinal reflexes was progressively understood since the role of muscle stretch reflex to generate muscle contraction was discovered by Liddell and Sherrington (1924), Delwaide and Oliver (1988) Descending influences control spinal reflexes by converging along with primary peripheral afferents on common interneuronal pool projecting to motoneurons. Imbalance of the descending inhibitory and facilitatory influences on muscle stretch reflexes is thought to be the cause of spasticity (Lundberg, 1975). These influences are discussed below.
There are five important descending tracts, of these, corticospinal tract originates from cerebral cortex. Other four come from closely neighboring parts in the brain stem and these are – Reticulospinal Vestibulospinal, Rubrospinal, and Tectospinal tracts. In human spastic paretic syndrome, the three important pathways are – corticospinal, reticulospinal, and vestibulospinal.
The four descending pathways which are important in spastic paretic syndrome are arranged as follows in the spinal cord:
Muscle tone is maintained by a controlled balance on stretch reflex arc by inhibitory influence of CST and dorsal RST and facilitatory influence (on extensor tone) by medial RST and to a lesser extent in humans by VST.
How does UMN lesion cause spasticity and associated phenomena? The major problem is a loss of control of the spinal reflexes. Spinal reflex activity is normally tightly regulated and if inhibitory control is lost, the balance is tipped in favor of excitation, resulting in hyperexcitability of the spinal reflexes. The problem is made difficult by the fact that individual patients have lesions affecting different pathways to different extent and that the subsequent adaptations in the spinal networks, as a result to the primary lesion, may vary considerably. The different spinal mechanisms – plateau potentials, reciprocal inhibition and presynaptic inhibition – may have different roles in different patients. It is likely that spasticity is not caused by a single mechanism, but rather by an intricate chain of alterations in different inter-dependent networks.
The fact that there is a period of shock, followed by a transition period when reflexes return, but are not hyperactive suggests that this is not just simply a question of switching off supraspinal inhibition, or altering the balance. It implies that there must be some sort of rearrangement, a kind of neuronal plasticity, occurring within the spinal cord, and most probably at the cerebral level as well. One possibility is sprouting of afferent axons (Raisman, 1969; Benecke, 1985; Raineteau and Schwab, 2001; Bareyre et al., 2004). Afferent fibers might sprout, attach to previously inhibitory synapses, and convert them to excitatory synapses. Alternatively there could be development of denervation hypersensitivity due to upregulation of receptors (Sravraky, 1961).
Spasticity may also be explained by changes in mechanical properties of muscles and not only by hyper-reflexia (Dietz et al., 1981; Thilmann et al., 1991). The increased mechanical resistance may be caused by alterations in tendon compliance and physiological changes in muscle fibers which affect functional movement of leg occurring at low angular velocities. Contractures are extreme effects of mechanical resistance which can be prevented by early treatment of hypertonia with botulinum toxin (BTX) in spastic cerebral palsy.
In conclusion, it needs to be mentioned that the progress being made in the electrophysiologic analysis of spinal control mechanisms in spasticity and measurement of spasticity are helpful for greater understanding of pathophysiology of the condition. Newly used drugs have multiple sites of actions (Delwarde and Pennisi, 1994). On the whole it seems highly likely that more than one pathophysiologic abnormality contributes to development of spasticity (Sheean, 2001; Nielsen et al., 2007).
The use of BTX in treatment of spasticity has already been mentioned. When injected at or near the motor point of affected muscle BTX binds to the SV2 receptor on the presynaptic membrane allowing for entry of the toxin into the axon terminal. Once inside the axon, BTX light chains act to impede exocytosis of acetylcholine (ACH). This allows for fusion of neurotransmitter-containing intra-axonal vesicles with the presynaptic membrane, resulting in extrusion of ACH into the synaptic cleft. The reduced presynaptic outflow of ACH at the neuromuscular junction causes diminution of muscle contraction. BTX reduces the frequency and quantity but not the amplitude of miniature endplate potential (MEPP). The motor EPP is reduced below the muscle membrane threshold and the ability to generate muscle fiber action potentials and subsequent contraction is diminished (Ney and Joseph, 2007).
Of the orally active agents, Baclofen is a centrally acting GABA analog. It binds to GABA receptor at the presynaptic terminal and inhibits muscle stretch reflex. Baclofen can also be used intrathecally.
Dantrolene interferes with the release of calcium from the sarcoplasmic reticulum of the muscle.
Tizanidine is an imidazole derivative with agonist action on alpha-2-adrenergic receptors in the central nervous system. The exact mechanism of its action in reduction of human muscle tone is not known but a central action can be speculated.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.